GUIDANCE DOCUMENT Product Monograph

Transcription

1 GUIDANCE DOCUMENT Published by authority of the Minister of Health Adopted Date 2016/06/17 Revised Date 2016/12/09 Effective Date 2017/06/09 Health Products and Food Branch

2 Our mission is to help the people of Canada maintain and improve their health. Health Canada The Health Products and Food Branch (HPFB) s mandate is to take an integrated approach to managing the healthrelated risks and benefits of health products and food by: Minimizing health risk factors to Canadians while maximizing the safety provided by the regulatory system for health products and food; and, Promoting conditions that enable Canadians to make healthy choices and providing information so that they can make informed decisions about their health. Health Products and Food Branch Minister of Public Works and Government Services Canada 2016 Également disponible en français sous le titre : Ligne directrice : Monographie de produit

3 Health Canada FOREWORD Guidance documents are meant to provide assistance to industry and health care professionals on how to comply with the policies and governing statutes and regulations. They also serve to provide review and compliance guidance to staff, thereby ensuring that mandates are implemented in a fair, consistent and effective manner. Guidance documents are administrative instruments not having force of law and, as such, allow for flexibility in approach. Alternate approaches to the principles and practices described in this document may be acceptable provided they are supported by adequate scientific justification. Alternate approaches should be discussed in advance with the relevant program area to avoid the possible finding that applicable statutory or regulatory requirements have not been met. As a corollary to the above, it is equally important to note that Health Canada reserves the right to request information or material, or define conditions not specifically described in this guidance, in order to allow the Department to adequately assess the safety, efficacy or quality of a therapeutic product. Health Canada is committed to ensuring that such requests are justifiable and that decisions are clearly documented. This document should be read in conjunction with the accompanying notice and the relevant sections of other applicable guidances. Revised Date: 2016/12/09; Effective Date: 2017/06/09 i

4 Health Canada DOCUMENT REVISION HISTORY Version Document Name Change Made Dates 1 Guidance for Industry: 2 : Initial Issuance of Guidance and Templates Overdosage section Addition of standard boxed message Adopted Date 2003/09/22 Effective Date 2004/10/01 Effective Date 2010/01/01 3 : 4 : Reporting Suspected Side Effects Administrative updates Part III: Patient Medication Information (PMI) Part III, formerly titled Consumer Information was revised to include plain language elements, including new language and formatting Part I: Health Professional Information Part II: Scientific Information Appendices A, B, C, D All 5 associated templates These sections were revised with plain language enhancements including reorganization of information Adopted Date 2013/09/12 Effective Date 2014/06/01 Adopted Date 2016/06/17 Revised Date 2016/12/09 Effective Date 2017/06/09 ii Revised Date: 2016/12/09; Effective Date: 2017/06/09

5 Health Canada TABLE OF CONTENTS 1 INTRODUCTION Purpose What Is a? Medical and Scientific Implications Regulatory Implications Prescribing Information Patient Medication Information When is a Required? Revisions Distribution Inquiries Guiding Principles Using the Template PREPARING A STANDARD PRODUCT MONOGRAPH General Instructions Style Guide Title Page Recent Major Label Changes Table of Contents PART I: HEALTH PROFESSIONAL INFORMATION Indications Patient Subsets Pediatrics Geriatrics Contraindications Serious Warnings and Precautions Box Location Dosage and Administration Dosing Considerations Recommended Dose and Dosage Adjustment Administration Reconstitution Missed Dose Overdosage Dosage Forms, Strengths, Composition and Packaging Warnings and Precautions Serious Warnings and Precautions Box Revised Date: 2016/12/09; Effective Date: 2017/06/09 iii

6 Health Canada Specific Subheadings Adverse Reactions Definitions and Terminology General Information Adverse Reaction Overview Clinical Trial Adverse Reactions Less Common Clinical Trial Adverse Reactions Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and other Quantitative Data Clinical Trial Adverse Reactions (Pediatrics) Post-Market Adverse Reactions Drug Interactions Serious Drug Interactions Box Overview Drug-Drug Interactions Drug-Food Interactions Drug-Herb Interactions Drug-Laboratory Test Interactions Drug-Lifestyle Interactions Action and Clinical Pharmacology Mechanism of Action Pharmacodynamics Pharmacokinetics Storage, Stability and Disposal Special Handling Instructions PART II: SCIENTIFIC INFORMATION Pharmaceutical Information Drug Substance Clinical Trials Efficacy and Safety Studies Pivotal Comparative Bioavailability Studies Microbiology Non-clinical Toxicology Supporting s PART III: PATIENT MEDICATION INFORMATION Introduction Language Style Guide Illustrations Readability and Usability Using the Template iv Revised Date: 2016/12/09; Effective Date: 2017/06/09

7 Health Canada General Opening Disclaimer About the Medication Warnings and Precautions Interactions Proper Use Side Effects Reporting Side Effects Storage More Information Date GLOSSARY Appendix A Preparing a for a Product with a Notice of Compliance with Conditions... A-1 Appendix B Preparing a for a Subsequent Entry Product (except for Schedule C and D Products)... B-1 Appendix C Preparing a for a Schedule C Product... C-1 Appendix D Preparing a for a Schedule D Product... D-1 Revised Date: 2016/12/09; Effective Date: 2017/06/09 v

8 Health Canada 1 INTRODUCTION 1.1 Purpose The purpose of this guidance document is to assist sponsors in developing product monographs with acceptable format and content. The product monograph is an integral part of New Drug, Supplement to a New Drug, Abbreviated New Drug and Supplement to an Abbreviated New Drug Submissions. A product monograph is intended to provide the necessary information for the safe and effective use of a new drug and also to serve as a standard against which all promotion and advertising of the drug can be compared. 1.2 What Is a? A product monograph is a factual, scientific document on a drug product that, devoid of promotional material, describes the properties, claims, indications, and conditions of use for the drug, and that contains any other information that may be required for optimal, safe, and effective use of the drug. A product monograph should include appropriate information respecting the name of the drug, its therapeutic or pharmacologic classification, its actions and/or clinical pharmacology, and its indications. The product monograph should also include: contraindications, dosage and administration, symptoms and treatment of overdosage, dosage forms, warnings, precautions, adverse reactions, drug interactions, effects on laboratory tests, storage and stability, special handling instructions, pharmaceutical information, information on clinical trials, microbiology, toxicology, and information for the patient. In addition, the product monograph should state both the dates of initial approval and revision. 1.3 Medical and Scientific Implications From a medical and scientific standpoint, the prime objective of a product monograph is to provide essential information that may be required for the safe and effective use of a new drug. As far as the health professional is concerned, the information provided should be as meaningful and helpful as possible. However, only those indications and clinical uses that are based on substantial evidence of efficacy and safety and that are the subject of a New Drug Submission, or an Abbreviated New Drug Submission, or a Supplement to either submission that has received a Notice of Compliance pursuant to Section C of the Food and Drug Regulations, should be included in the product monograph. The product monograph is not intended to serve as a repository of all information currently available on a drug. The product monograph is based primarily on data submitted by a sponsor and evaluated by Health Canada as part of the regulatory drug review and authorization process. As a result, it may not reflect the entire existing body of evidence. Revised Date: 2016/12/09; Effective Date: 2017/06/09 1

9 Health Canada 1.4 Regulatory Implications The product monograph, as a document, will be included by Health Canada as part of the Notice of Compliance respecting a New Drug Submission or, when appropriate, a Supplement to a New Drug Submission, an Abbreviated New Drug or a Supplement to an Abbreviated New Drug Submission. The product monograph serves as a standard against which all promotional material, or advertising distributed or endorsed by the sponsor about the drug can be compared. The product monograph serves the following purposes: It contains all the representations to be made in respect of the new drug as required by paragraph C (2)(k) and C (2)(h) of the Food and Drug Regulations. It fulfils the requirements for adequate directions for use for new drugs included in a number of Sections having to do with labelling in Parts C and G of the Food and Drug Regulations. It identifies the information that is to be provided on request when a package insert is not included with a new drug product and a health professional requests information relevant to clinical use. It identifies the information that should be provided to the patient respecting the use of that product [that is (i.e.) Part III, Patient Medication Information]. It establishes the limitations/parameters for all advertising, representations, and promotional or information material distributed or otherwise endorsed by the sponsor. Subsection C (2) of the Food and Drug Regulations prohibits the advertising of a new drug for any use of the drug or for any claim that has not been the subject of a cleared submission. As this information is represented in the product monograph, no professional or published literature should be quoted, distributed, or otherwise provided by the sponsor if it refers to claims or indications for use that are not supported by the current product monograph Prescribing Information The information described in Part I (Health Professional Information) of the product monograph contains prescribing information, and serves the following purposes: It identifies the information to be provided if a package insert is included with a new drug product. 2 Revised Date: 2016/12/09; Effective Date: 2017/06/09

10 Health Canada It identifies information to be provided as part of all professional material and that may be used for promotional and advertising purposes, other than in the case of reminder notices. In addition to Part I, the information described in Part III (Patient Medication Information) may also be provided as part of the package insert for a new drug product Patient Medication Information The information described in Part III (Patient Medication Information) of the product monograph contains information for the patient. This portion of the product monograph identifies the information that is to be provided to the patient or consumer either at the time of dispensing as a separate document, or as a package leaflet. 1.5 When is a Required? A draft copy of the proposed or revised product monograph should be included in the master volume when a New Drug, Supplement to a New Drug, Abbreviated New Drug or Supplement to an Abbreviated New Drug Submission is filed for either a prescription or nonprescription drug. Health Canada will advise the sponsor if the New Drug Submission or Supplement to a New Drug Submission is judged to be incomplete in complying with the requirements of Section C or C of the Food and Drug Regulations. 1.6 Revisions A product monograph can be revised by filing an acceptable Notifiable Change or Supplement to a New Drug Submission or Supplement to an Abbreviated New Drug Submission. Revisions should be initiated by the sponsor whenever significant updating of the product monograph is required in order to incorporate additions or other changes related to safety (particularly with respect to warnings, precautions, adverse reactions, and mode of administration) that may be necessary as a result of newly available information. The product monograph should also be revised whenever substantial information is available to support significant new indications or when other changes or deletions in the indications and conditions of use are required as a result of additional available information. In some instances, it may be necessary to inform the health professional or the patient about special hazards or to issue special warnings before there is an opportunity to revise the product monograph. Pursuant to paragraph C (f) of the Food and Drug Regulations, Health Canada may request that the sponsor revise the product monograph if, on the basis of new information, it is considered to be false, misleading, or incomplete in any respect. Whenever periodic reports on a Revised Date: 2016/12/09; Effective Date: 2017/06/09 3

11 Health Canada new drug are requested pursuant to paragraph C (a) of the Food and Drug Regulations, the sponsor should determine whether significant changes should be made in the product monograph as a result of the additional information available. 1.7 Distribution A copy of the most recently updated product monograph (including the Patient Medication Information) should be provided by the sponsor to health professionals whenever they request prescribing information or other information relevant to the clinical use of the new drug. For products that have received a Notice of Compliance (NOC) and are marketed, the product monograph must be available in both official languages. The Health Professional Information portion of the product monograph may also be made available as a package insert. This portion should therefore be provided in connection with the promotion or advertisement of the drug or included in reference manuals distributed or endorsed by the sponsor. In addition the Patient Medication Information may also be provided as part of the package insert for a new drug product. A copy of the most recently updated product monograph (including the Patient Medication Information) should be provided to health professionals prior to, or coincident with, the first direct promotion or marketing of a new drug, and to any health professionals to whom the sponsor sells a new drug before it is generally available. Additional information may be found in Health Canada s : Labelling of Pharmaceutical Drugs for Human Use. 1.8 Inquiries The Regulatory Project Management Division of the Therapeutic Products Directorate or the Office of Regulatory Affairs of the Biologics and Genetic Therapies Directorate may assist sponsors with questions concerning the filing of a draft product monograph. General inquiries may be directed to RPM_Division-GPR_Division@hc-sc.gc.ca or BGTD_ORA@hc-sc.gc.ca. 1.9 Guiding Principles A product monograph should be prepared with the following guiding principles as a basis for the information: Avoid duplication of information. Wherever possible, information should only be presented once in the product monograph. Key information should be easy to locate. 4 Revised Date: 2016/12/09; Effective Date: 2017/06/09

12 Health Canada Information should be presented in a consistent format to facilitate ease of retrieval, particularly in an electronic environment. This requires the standardization of terminology and the inclusion of hyperlinks for searching Using the The main part of this document is referred to as the "core document" and it provides guidance for preparing a standard product monograph. For other drugs that have specific information requirements, please consult the following appendices: Notice of Compliance with Conditions (NOC/c) Subsequent Entry Products (except for Schedule C and D products) Schedule C Products Schedule D Products Appendix A Appendix B Appendix C Appendix D If more than one appendix applies to a product monograph (for example, a biologic that also has an NOC/c), the requirements from both need to be incorporated into the product monograph Template A product monograph should be prepared in the same software format as the other submission documents. An electronic template (in Microsoft Word format) for a standard monograph, as well as those listed above, is provided with this guidance document. Instructions that may be useful in preparing the product monograph are contained within square brackets [..] and are to be removed by the sponsor during preparation. Information to be included in the product monograph is contained within pointed brackets <...>. 2 PREPARING A STANDARD PRODUCT MONOGRAPH Each product monograph will consist of three distinct parts: Part I: Health Professional Information Contains information required for the safe and appropriate prescribing, dispensing and administering of the drug product. Revised Date: 2016/12/09; Effective Date: 2017/06/09 5

13 Health Canada Part II: Part III: Scientific Information Contains more in-depth scientific/research information such as non-clinical toxicology and data from animal studies and human clinical trials. It complements and extends the information contained in Part I. Patient Medication Information Contains information derived from Parts I and II that helps the patient understand what the medication is, how to use it and what the potential side effects are. It is also intended to serve as a guide for health professionals to easily identify the information needed for counselling patients. It is presented in a language and format that is appropriate for a patient audience, including the general public. Part III is required for all drugs, regardless of the location of use [for example (e.g.), hospital] or method of administration (e.g., by a third party). 2.1 General Instructions The guidance document presents the sections of the product monograph in the order that they should appear. Health Canada recognizes that this guidance document may not address the information requirements for all drugs and individual judgement remains critical in assessing how or whether to present the information. If a section is not included, a rationale should be provided by the sponsor. "Health professional" is the preferred term that should be used in Part I (Health Professional Information) and Part II (Scientific Information) of the product monograph when referring collectively to professionals. It is also intended to be used in place of singular terms such as: health care provider, health care practitioner, etcetera (etc.). For pharmaceutical prescription products and those administered or obtained through a health professional, the product monograph should be supplied to Health Canada in both official languages (i.e., Canadian English and French). Please refer to the Guidance Document Questions and Answers: Plain Language Labelling Regulations for more details regarding the timing of the submission of these documents. Suggested standard statements are provided for sponsors to use in the preparation of the product monograph. They are identified in the guidance document by the preceding instruction: "the following or similar statement". If a standard statement is applicable, the sponsor is required to use it. If a statement does not fit a particular product, the sponsor may amend it. Words or phrases that lack a commonly understood meaning (e.g., imprecise quantitative terms), are not easily defined, are vague, misleading, or promotional in tone should be avoided (e.g., unique, novel, convenient, potent). 6 Revised Date: 2016/12/09; Effective Date: 2017/06/09

14 Health Canada 2.2 Style Guide Paper: 21.6 x 27.9 centimetre (8½ x 11") portrait orientation Margins: 2.5 centimetre (1") top, bottom and sides Line spacing: single Font: Parts I, II and III: Sans Serif type fonts (e.g., Calibri 12 point, Arial 11 point) Patient Medication Information leaflet: Sans Serif type fonts, text - 10 point, tables - 9 point. Justification: left Page numbers: on bottom right hand side Start each Part on a new page Heading format: see template When a cross-reference is included, a hyperlink should be built in. For Parts I and II, the first use of the brand name should be followed by the proper name (or common name, where there is no proper name) in final dosage form, in parentheses. In describing the drug's actions, pharmacology, and toxicology, the proper name (or common name, where there is no proper name) in final dosage form should be used. For Part III (Patient Medication Information), brand name should be used to describe the drug, or if there is no brand name, use the proper name of the drug in final dosage form. Where there is no proper name, use the common name in final dosage form. Upper case font and bold type face should be used for emphasis sparingly. Paragraph numbering should not be used. If abbreviations are used in a table, a legend should be included at the bottom of table. Additional style instructions are provided for the Patient Medication Information (see Section 5.3). 2.3 Title Page The title page should bear the following information in the following sequence: a) the words ", Including Patient Medication Information", b) the scheduling symbol (e.g., Pr, N, T/C), as applicable, c) the brand name of the drug product, d) the proper or common name of the drug product(s) in final dosage form, e) the strength(s), dosage form(s) and route(s) of administration, Revised Date: 2016/12/09; Effective Date: 2017/06/09 7

15 Health Canada f) where there is no proper or common name for the drug product in final dosage form, list all medicinal ingredients by their proper or common name, along with the dosage form of the final drug product, g) the pharmaceutical standard of the drug product (e.g., prescribed, pharmacopeial or professed), if applicable, h) the therapeutic, diagnostic or pharmacological classification and code in accordance with the World Health Organization's Anatomical Therapeutic Chemical (ATC) index 1, i) the name, place of business and website of the sponsor, and, when appropriate, the name and place of business of the distributor in Canada, j) date: for a new product monograph use the date of initial approval. For subsequent revisions to any part of the product monograph, also include the most current revision date; and, k) the submission control number. When the title page would normally be omitted (i.e., in package inserts or advertising copy) items a to k should be repeated on page 1 of the product monograph. Presentation: see template 2.4 Recent Major Label Changes List the section headings in the product monograph where any major label changes related to safety and efficacy have been made within the past 24 months, under the following sections: Serious Warnings and Precautions Box; Indications; Contraindications; Dosage and Administration; Warnings and Precautions; Major label changes include Level I changes filed with a Supplement to a New Drug or Supplement to an Abbreviated New Drug Submission, or a Level II Notifiable Change for either a prescription or non-prescription drug. Criteria for determining the levels or types of changes are described in both the : Post Notice of Compliance (NOC) Changes: 1 ATC/DDD Index 2014 ( 8 Revised Date: 2016/12/09; Effective Date: 2017/06/09

16 Health Canada Safety and Efficacy Document and the : Post Notice of Compliance (NOC) Changes: Quality Document. The headings of the changed sections (including subheadings where applicable) should be listed in the order in which they appear in the product monograph, on separate lines. The section numbers should be included as well, along with the dates the changes were authorized. Dates should be in the following format: (MON/YYYY). For example: Warnings and Precautions, Pregnant Women (6.1.1) 12/2013 If there were multiple changes under the same heading or subheading within the past 24 months, only list the date of the newest change. If there were changes under more than one subheading within the same section during the last 24-month period, list each of these changes separately. For example: Warnings and Precautions, Pregnant Women (6.1.1) 12/2013 Warnings and Precautions, Pediatrics (6.1.3) 09/2014 All major label changes made in the last 24 months should be indicated within the body of the product monograph where they occur, by a vertical line on the left edge of the page. Presentation: list (see template) 2.5 Table of Contents The product monograph should include a table of contents with page numbers. Section headings are standard and do not change; however, subsection headings should be included in the table of contents where applicable. All section and subsection headings should be numbered and hyperlinked to the corresponding area within the product monograph. Presentation: see template 3 PART I: HEALTH PROFESSIONAL INFORMATION 3.1 Indications The indications listed in this section should be based on substantial evidence of the drug product's efficacy and safety, derived from adequately designed and conducted clinical studies. Only those indications authorized by Health Canada can be included. An indication should specifically refer to the disease(s), medical condition(s) or prophylactic measure(s) the drug is authorized to treat or manage and include the patient population that the drug is intended to treat or manage (e.g., patients with atrial fibrillation, pediatrics). Revised Date: 2016/12/09; Effective Date: 2017/06/09 9

17 Health Canada Only those diagnostic test kits that have been licensed for sale by Health Canada can be named in this section. Any relevant information about the kit should be included in the Clinical Trials section. Where applicable, a statement should be included to indicate that the drug product is intended for use as an adjunct to other forms of management of the condition (e.g., lifestyle modification in osteoporosis). When appropriate, this section should also describe the optimal use of the drug and the limitations of usefulness. When the genotype of the patient or that of an infectious agent will affect the treatment outcome, relevant information should also be included in this section. Any special restrictions with respect to the use (e.g., specific health professionals) and/or distribution of the drug (e.g., a hospital setting, ambulance), which may be required on a temporary or permanent basis, should be declared in this section. If there are situations where the use of this drug product is not therapeutically appropriate (e.g., maintenance versus acute therapy), this information should be included. It is beyond the scope of the product monograph to provide information on the disease targeted by the indications. Presentation: bullet list (for indications) and narrative Patient Subsets Pediatrics For indications authorized for adults in general, a statement regarding use in the pediatric population should be included. The term pediatric generally pertains to persons between birth and 18 years of age, but it is recognized that this may not apply to all drug products 2, therefore the Pediatric subtitle should include the age upon which the pediatric recommendation is based. For example, 12 years of age should be used if the clinical trials included only children up to the age of 12. If pediatric patients were included on the basis of criteria other than age (e.g., by weight, without a specified age range), this should be reflected here instead. One of the following or similar statements should be used: 2 ICH Topic E 11Clinical Investigation of Medicinal Products in the Paediatric Population, January Revised Date: 2016/12/09; Effective Date: 2017/06/09

18 Health Canada Pediatrics (age range): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of [Brand name] in pediatric patients has been established; therefore, Health Canada has authorized an indication for pediatric use. [Include cross-reference to relevant sections.] or Pediatrics (age range): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use. or Pediatrics (age range): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of [Brand name] in pediatric patients has not been established; therefore, Health Canada has not authorized an indication for pediatric use. [Include cross-reference to relevant sections.] Any information relating to clinical trials which support the Health Canada authorized indication(s) should be included in the Clinical Trials section of Part II: Scientific Information Geriatrics For indications authorized for adults in general, a statement regarding use in the geriatric population may be included. The term geriatric generally pertains to persons over 65 years of age but it is recognized that this may not apply to all drug products, therefore, if applicable, the Geriatric subtitle should include the age upon which the geriatric recommendation is based. For example, 75 years of age would be used if the study data included only the frail elderly. One of the following or similar statements may be used: Geriatrics: No data are available to Health Canada; therefore, Health Canada has not authorized an indication for geriatric use. or 3.2 Contraindications Geriatrics: Evidence from clinical studies and experience suggests that use in the geriatric population is associated with differences in safety or effectiveness. This section should describe absolute contraindications, meaning those situations in which the drug should not be used because the risk outweighs any potential therapeutic benefit. Revised Date: 2016/12/09; Effective Date: 2017/06/09 11

19 Health Canada For contraindicated drug-drug or drug-food interactions a brief statement should be included here with a cross-reference to the detailed information in Drug Interactions. For hypersensitivity reactions, the following or similar statement should be used: Presentation: bullets <Proper name> is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see Dosage Forms, Strengths, Composition and Packaging. 3.3 Serious Warnings and Precautions Box Location In those cases where there is a Serious Warnings and Precautions Box, it is to be located immediately following the Contraindications section (for more information, see section 3.7 Warnings and Precautions). 3.4 Dosage and Administration Dosing Considerations This subsection should briefly list the safety issues to consider when developing a dosage regimen in an individual patient (e.g., renal disease, age, concomitant therapy, genetic polymorphism, titration). Where different dosage forms are available, if the dosages are not equivalent the conversion value should be stated (e.g., changing from intravenous to oral therapy where a ratio other than 1:1 exists). Presentation: bullets Recommended Dose and Dosage Adjustment This subsection should provide detailed and practical information on the recommended dosage. The subsection should include: dosage schedules, the initial dose, the optimal method of titrating dosage, the dosage range, maximum daily dose, maintenance dosage, duration of treatment and drug discontinuance. When applicable, dosages should be provided for each indication, route of administration and dosage form. Guidance should be given on the dosage adjustments necessary when administering the drug in special populations for whom the product is indicated (e.g., children, elderly) or in the presence of pathologies (e.g., renal disease, hepatic disease, genetic polymorphism). When an age descriptor is used (e.g., children, pediatrics), the age range 12 Revised Date: 2016/12/09; Effective Date: 2017/06/09

20 Health Canada should be specified. In the absence of a Health Canada authorized pediatric indication, this subsection should emphasize that the product is not indicated in the pediatric population. The following or similar statement should be used: Health Canada has not authorized an indication for pediatric use. [Include crossreference to relevant sections, if applicable.] If no dosage adjustments are required a statement to that effect should be included (e.g., No dosage adjustment required in hepatic or renal impairment). Presentation: narrative Administration This subsection should include details concerning the methods of administration, particularly for parenteral products or for other unique formulations such as inhalation devices, implants, and transdermal formulations. Where aseptic techniques are required, this information should be included. Use in combination with other drugs (e.g., in same intravenous solution) should also be described. Special considerations for administering the drug with respect to the formulation should be specified (e.g., do not crush; if capsule contents can be sprinkled; etc.). For parenteral products or those with other unique formulations, details of the administration technique for each route should be given, including use in infusion or lavages, etc. The time of day for optimal drug effect should be indicated (e.g., evening, morning, etc.) where applicable. Timing of administration of a dose with respect to food should be indicated using the following or similar statements: Empty stomach, 1 hour before or 2 hours after meals; Before meals, usually 15 to 30 minutes before meals; Empty stomach preferably, may be taken with food if gastric upset occurs; With or without food, may be given without regard to meals; Consistently with or without food as presence or absence of food may alter bioavailability. Presentation: narrative and/or table Revised Date: 2016/12/09; Effective Date: 2017/06/09 13

21 Health Canada Reconstitution Oral Solutions This subsection, which is essential for all drug products that require reconstitution prior to patient administration, should list all recommended diluents for reconstitution. Directions for reconstitution should include the volume and type of diluents to be added and the approximate volume and concentration of the resulting product. The recommended storage period and conditions for each solution should be stated (include cross-reference to Storage, Stability and Disposal). Presentation: narrative and/or table Parenteral Products For parenteral drugs requiring reconstitution or dilution before use, it is recommended that the relevant information be presented in a table under subheadings of the recommended routes of administration. The recommended diluent for each proposed route of administration should be included under each subheading. A reconstitution table should include the following four columns: vial size; volume of diluent to be added to vial; approximate available volume; nominal concentration per millilitre. For intravenous use, information should be separated for: direct intravenous injection; intermittent intravenous infusion; and continuous intravenous infusion. Any specific precautions should be specified below the table. For infusions, all common intravenous infusion fluids with which the drug has been shown to be incompatible, and the method of preparing the dilutions, should be listed. The recommended storage period and conditions for each preparation should be stated (include cross-reference to Storage, Stability and Disposal). Presentation: table and narrative (see template). 14 Revised Date: 2016/12/09; Effective Date: 2017/06/09

22 Health Canada Missed Dose This subsection should provide guidance on the actions to be taken in the event that a patient misses a dose. Presentation: narrative 3.5 Overdosage This section should include the following: a description of the signs and symptoms of overdose; current recommended management of overdosage (e.g., antidotes and/or other clinical interventions required); the human lethal dose (if available), and the maximum dose reported with recovery, with or without residual damage; and procedures that, by experience with this or similar type drugs, are known or reasonably expected to be unnecessary or unsuitable (e.g., those that may be hazardous to the patient). Presentation: narrative The following boxed statement is to be added at the end of the Overdosage section: For management of a suspected drug overdose, contact your regional poison control centre. 3.6 Dosage Forms, Strengths, Composition and Packaging The following information should be included in a summary table at the beginning of this section: all authorized dosage forms, and strengths of each form in terms of the concentration of medicinal ingredient (e.g., suspension/50 mcg [micrograms] per metered spray) the recommended route of administration for each form where applicable, the composition (e.g., components making up the capsule shell, coating, patch, etc.) should also be included for each strength of each dosage form a qualitative, alphabetical listing of all non-medicinal ingredients. The terminology for the routes and forms will be in accordance with those published by Health Canada. Revised Date: 2016/12/09; Effective Date: 2017/06/09 15

23 Health Canada Different strengths of the product containing identical ingredients should be grouped together whenever possible. Different strengths containing different ingredients should be listed on a separate line. Presentation: table (see template) A complete description of each authorized dosage form s physical characteristics should be provided, including identifiable markings. Other items such as those required for administration or quality control, reconstitution, elution etc. should also be included. Other unique formulation information should be included in this section (e.g., inert components remain intact after elimination). A description of the type and size of all authorized packaging formats should be included (e.g., "supplied in bottles of 100's, 500's, and 1,000's and in blister packs of 100's"). Any additional packaging information (e.g., latex), or potential for cross-contamination during manufacturing that may impact patient safety should be described (e.g., peanuts, gluten). Presentation: narrative 3.7 Warnings and Precautions This section contains information about all serious effects that may pose a hazard to the patient, as well as precautions to be exercised by the health professional or by the patient in order to ensure safe and effective use of the drug Serious Warnings and Precautions Box Clinically significant or life-threatening safety hazards when taking the drug should be highlighted in the Serious Warnings and Precautions Box. Information for the Serious Warnings and Precautions Box may be drawn from any section of the product monograph and will be determined in consultation with Health Canada. Information related to clinically significant or life-threatening product class-related adverse reactions should also be included, if applicable, with a cross-reference to the Adverse Reaction section. If there are no serious warnings or precautions, this box is omitted. A brief statement is provided in the Serious Warnings and Precautions Box with a crossreference to the applicable section of the product monograph where complete details are provided. The text in the box should generally not exceed 20 lines. 16 Revised Date: 2016/12/09; Effective Date: 2017/06/09

24 Health Canada Statement examples: Drug interactions with digoxin, phenytoin (see Drug Interactions section); Liver toxicity (see Hepatic section below); Should only be administered by health professionals experienced with cancer chemotherapeutic drugs (see Indications). Information on products requiring administration by a specialized health professional or in a restricted setting, should also be highlighted in the Serious Warnings and Precautions Box (i.e., a brief statement) with a cross-reference to the more detailed information in the Indications section. The Serious Warnings and Precautions box is to be located immediately following the Contraindications section. Include the following or similar statement in the Warnings and Precautions section: Please see the Serious Warnings and Precautions Box at the beginning of Part 1: Health Professional Information. Presentation: bullet form within a box (see template) Specific Subheadings Subheading should be used to group the information in this section. Subheadings should be alphabetically ordered as presented below, and only used where applicable. For a particular subheading, if there are no effects that may pose a hazard to the patient or precautions to be exercised by the health professional or patient in order to ensure safe and effective use of the drug, then the subheading should be omitted. Additional subheadings may also be used. Information presented within subheadings should be in decreasing order of importance. General: This subsection contains information that does not fall under the subheadings listed below. Carcinogenesis and Mutagenesis: This subheading should include only human data where there is evidence that the drug is carcinogenic or mutagenic. Where there is only animal data, a cross-reference to the animal data in the Non-clinical Toxicology section should be provided. Revised Date: 2016/12/09; Effective Date: 2017/06/09 17

25 Health Canada Cardiovascular Dependence/Tolerance: This subheading should include effects resulting from both physical and psychological dependence. The amount of drug, duration of time taking the drug and characteristics of the dependence and withdrawal should be described. Treatment of the effects of the dependence should be provided. Driving and Operating Machinery: This subheading should include any effects that may impair performance of a task requiring special attention, including driving and operating machinery, along with the following or similar statement: Due caution should be exercised when driving or operating a vehicle or potentially dangerous machinery. Ear/Nose/Throat Endocrine and Metabolism: This subheading should specify genetic polymorphism where applicable. Gastrointestinal Genitourinary Hematologic Hepatic/Biliary/Pancreatic: When possible, idiopathic versus metabolic liver failure should be described. Immune: This subheading should include effects resulting from altered immune reactivity, clinically expressed as either immune activation or immune suppression. Immunogenicity or allergenicity should be given special consideration if applicable. Monitoring and Laboratory Tests: This subsection should include important monitoring parameters (e.g., blood pressure), observations, laboratory or other tests required to monitor response to therapy and possible adverse reactions. The frequency of monitoring before, during and after therapy should be included. Information regarding the range of normal and abnormal values expected in a particular situation should be provided. Appropriate response to particular laboratory values should be included. 18 Revised Date: 2016/12/09; Effective Date: 2017/06/09

26 Health Canada Neurologic Ophthalmologic Peri-Operative Considerations: This subsection should include information on management before, during and after surgery. Practical details on drug discontinuation or dosage adjustment should be provided. Psychiatric: Behavioural changes (e.g., suicidal ideation) should be included in this subsection. Renal Respiratory Sensitivity/Resistance Sexual Health Reproduction: Where applicable, include instructions for pregnancy prevention/contraception and information about Pregnancy Registries. Function: Include effects on sexual desire, erection, orgasm and ejaculation. Fertility: A summary of relevant information on effects of the drug on fertility from animal or human exposure should be included under this subheading. Where there is absence of information, clearly state that no data exist. Skin: Where applicable, human photosensitivity (photoallergic or phototoxic) reactions should be included. Where there is only non-clinical data, a cross-reference to the Nonclinical Toxicology section should be provided. Special Populations Pregnant Women: The type of data should be briefly stated (human or animal) and the recommendation (e.g., avoid in a particular trimester) for prescribing the drug safely should be given. Teratogenic and nonteratogenic effects on the fetus should be included (e.g., withdrawal symptoms, hypoglycemia). If contraindicated in pregnancy, this should be included in this subsection and the Contraindications section. Include the following information, when available: Revised Date: 2016/12/09; Effective Date: 2017/06/09 19

27 Health Canada Disease-associated maternal and/or embryo/fetal risk Maternal adverse reactions Fetal/Neonatal adverse reactions Labour or delivery Include a cross-reference to the Dosage and Administration section when there are dose adjustments during pregnancy and the postpartum period. The extent of exposure in pregnancy during clinical trials should be included: Wide: >1,000 pregnancies 2 ; Limited: <1,000 pregnancies; Very Limited: individual cases only; No experience. It should be indicated when the drug is not absorbed systemically and not known to have potential for indirect harm to the fetus. Breast-feeding: Where a drug is absorbed systemically, information about the excretion of the drug in human milk and effects on the nursing infant should be included. Adverse reactions expected in the infant should be provided and suggested measures to avoid high level exposure to the infant should be presented. The potential for serious adverse reactions or tumourgenicity should be clearly stated. In the absence of human data, pertinent animal data should be included (e.g., adverse reactions, concentration detected in the milk plasma ratio) and the following or similar statement should be used: It is unknown if the drug is excreted in human milk. Because many drugs are excreted in human milk precaution should be exercised. Pediatrics: This subsection should contain specific monitoring and hazards associated with pediatric use of the drug. The term pediatric generally pertains to persons between birth and 18 years of age, but it is recognized that this may not apply to all products, therefore the Pediatric subtitle should include the age upon which the pediatric recommendation is based. For example, 12 years of age should be used if the clinical trials included only children up to the age of 12. If pediatric patients were included on the basis of criteria other than age (e.g., by weight, without a specified age range), this should be reflected here instead. 2 Extent of exposure categories are based on Council for International Organizations of Medical Sciences (CIOMS). 20 Revised Date: 2016/12/09; Effective Date: 2017/06/09

28 Health Canada In the absence of a Health Canada authorized pediatric indication, this subsection should repeat that the product is not indicated in the pediatric population. One of the following or similar statements should be used: Pediatrics (age range): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use. or Pediatrics (age range): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of [Brand name] in pediatric patients has not been established; therefore, Health Canada has not authorized an indication for pediatric use. [Include cross-reference to relevant sections.] Information about specific known safety risks associated with use of the product in the pediatric population should be reflected here (regardless of indication status), indicating the age range impacted, where known. Warnings should focus on events which are different from, or more severe than those seen in adults. An accompanying statement should explain that warnings applicable to adults are also relevant to pediatric use. Presentation of short-term versus long term exposure warnings may be relevant, if there are differences. Geriatrics: This subsection should contain specific monitoring and hazards associated with geriatric use of the drug. Cross-reference to renal and hepatic subheadings where appropriate. The term geriatric generally pertains to persons over 65 years of age but it is recognized that this may not apply to all products, therefore the Geriatric subtitle should include the age upon which the geriatric recommendation is based. For example, 75 years of age would be used if the study data included only the frail elderly. 3.8 Adverse Reactions Definitions and Terminology The application of the Adverse Reaction section of the guidance depends in part on the interpretation of the following terms: adverse reaction, adverse event, and serious adverse reaction. Adverse reaction, for the purpose of this guidance, is an unintended event, reasonably associated with the use of a drug and conforms to the regulatory definition of adverse drug reaction 3. 3 C , Food and Drug Regulations Revised Date: 2016/12/09; Effective Date: 2017/06/09 21